Acinetobacter baumannii has emerged as a major nosocomial pathogen that can cause ventilator associated pneumonia (VAP) and bacteremia, with associated mortality rates as high as 60% among susceptible patient populations. The high rates of A. baumannii associated morbidity and mortality have been largely attributed to the emergence of antibiotic resistance that has compromised the effectiveness of currently available antibiotics. The Centers for Disease Control and Prevention recently reported that 63% of all A. baumannii U.S. infections are caused by multi-drug resistant strains that are resistant to three or more classes of antibiotics and strains that are resistant to all current classes of antibiotics have recently been identified in the U.S. and elsewhere.
A. baumannii antibiotic resistance is mediated by an expansive repertoire of enzymatic determinants, such as β-lactamases, and efflux pumps that extrude toxic agents, including antibiotics, from the cell. With regard to the latter, the organism has been shown to harbor representatives of each of the five bacterial drug efflux pump families. For instance, CraA and AmvA are major facilitator superfamily (MFS) pumps that are proposed to efflux chloramphenicol and erythromycin, respectively; AbeM is a multidrug and toxic compound extrusion (MATE) family protein that effluxes aminoglycosides, quinolones, and chloramphenicol; AbeS is a small multidrug resistance (SMR) family pump that confers resistance to erythromycin and novobiocin as well as low level tolerance to aminoglycosides, quinolones, tetracycline and trimethoprim; AdeABC, AdeFGH, and AdeIJK are resistance nodulation division (RND) family pumps that have been associated with resistance to aminoglycosides, β-lactams, fluoroquinolones, tetracyclines, tigecycline, macrolides, chloramphenicol, and trimethoprim. Furthermore, A. baumannii is also known to harbor several ABC family transporters and horizontally acquired Tet efflux pumps belonging to the MFS that confer tetracycline resistance.
In addition to the aforementioned well-characterized efflux pumps, A. baumannii is reported to harbor an array of additional putative efflux pumps that may confer antibiotic resistance. For instance, the common laboratory strains, AYE and ATCC17978 contain 46 and 73 genes, respectively, that are annotated as putative drug efflux pumps. It remains to be seen if these factors do indeed modulate antibiotic tolerance or what endogenous- or exogenous-cues modulate their activity. Nonetheless, recent studies suggest that they are likely to have clinical significance. It has been found that 18 previously-uncharacterized putative drug efflux associated factors were significantly upregulated and conferred resistance to levofloxacin and amikacin during A. baumannii growth in physiologically relevant salt conditions. Likewise, A. baumannii grown in human serum was found to induce expression of approximately 22 drug efflux-associated genes and corresponded to efflux mediated tolerance to minocycline at levels that are clinically relevant. Such regulated changes efflux pump expression and, consequently, activity in response to host-associated environmental cues is thought to temporarily increase a bacterium's ability to survive antibiotic challenge and is hypothesized to allow otherwise clinically defined antibiotic susceptible strains to resist antibiotic insult; this phenomenon has recently been termed adaptive efflux-mediated resistance.